? ? Lung cancer is a major health concern with a very high mortality rate, afflicting approximately 170,000 people each year in the United States. Because most lung cancer patients are diagnosed at a late stage of the disease and available therapies are usually ineffective, the prognosis is very poor for most lung cancer patients. Theoretically, blockage of the multiple-step process of the progression from preinvasive disease to malignancy will reduce the incidence of advanced lung cancer. Therefore, development of effective prevention agents against lung cancer is critical for reducing mortality. In this study, we will focus on the flavonoid luteolin (3',4',5,7-tetrahydroxyflavone) as a potential lung cancer chemoprevention agent. Our preliminary studies demonstrate that the flavonoid luteolin selectively kills transformed but not normal lung cells and that reactive oxygen species (ROS) accumulation is essential for the luteolin-induced cytotoxicity in lung cancer cells. To establish the basis of future studies on the activity and mechanism of luteolin in lung cancer prevention, we plan to determine the underlying mechanism by which luteolin kills lung cancer cells in an in vitro cell culture system. The hypothesis driving this application is that luteolin-induced ROS mediates activation of c-Jun N- terminal kinase (JNK), which subsequently triggers activation of apoptosis pathways in transformed lung cells. This activation of apoptosis contributes to the chemopreventive activity of luteolin against lung cancer. We will test this hypothesis in the following specific aims: 1) to determine the mechanism by which luteolin induces ROS accumulation in lung cancer cells, 2) to determine the mechanism by which luteolin induces apoptosis in lung cancer cells, and 3) to determine the mechanism of selective cytotoxicity of luteolin in lung cancer cells. The success of this project would lead to development of future studies in animals and humans to test the preventive activity and mechanism of luteolin against lung cancer in vivo, which may lead to the clinical application of luteolin for human lung cancer prevention. ? ? ?
